Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma.

Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.

BDNF release and signaling are required for the antidepressant actions of GLYX-13.

Conventional antidepressant medications, which act on monoaminergic systems, display significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. GLYX-13 is a novel glutamatergic compound that acts as an N-methyl-D-aspartate (NMDA) modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine GLYX-13 produces rapid antidepressant actions in depressed patients and in preclinical rodent models. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been characterized. Here we use a combination of neutralizing antibody (nAb), mutant mouse and pharmacological approaches to test the role of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TrkB) signaling in the actions of GLYX-13. The results demonstrate that the antidepressant effects of GLYX-13 are blocked by intra-medial prefrontal cortex (intra-mPFC) infusion of an anti-BDNF nAb or in mice with a knock-in of the BDNF Val66Met allele, which blocks the processing and activity-dependent release of BDNF. We also demonstrate that pharmacological inhibitors of BDNF-TrkB signaling or of L-type voltage-dependent Ca2+ channels (VDCCs) block the antidepressant behavioral actions of GLYX-13. Finally, we examined the role of the Rho GTPase proteins by injecting a selective inhibitor into the mPFC and found that activation of Rac1 but not RhoA is involved in the antidepressant effects of GLYX-13. Together, these findings indicate that enhanced release of BDNF through exocytosis caused by activation of VDCCs and subsequent TrkB-Rac1 signaling is required for the rapid and sustained antidepressant effects of GLYX-13.

The Role of PD-1 Positivity in the Tumour Nest on Clinical Outcome in Upper Tract Urothelial Carcinoma Patients Treated with Radical Nephroureterectomy.

AIMS: The role of PD-1 (programmed cell death 1) expression on the clinical outcome of upper tract urothelial carcinoma has not yet been elucidated in detail. MATERIALS AND METHODS: PD-1 expression was immunohistochemically examined in 181 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy. A part of PD-1 protein expression in the tumour periphery and tumour nest was evaluated separately. The PD-1-positive cells were counted in the area showing the highest density of PD-1 expression at a magnification of 400×. RESULTS: PD-1 staining in the tumour nest was low in 137 (75.7%) and high in 44 (24.3%) patients. PD-1 staining in the tumour periphery was low in 78 (43.1%) and high in 103 (56.9%) patients. The 5 year progression-free survival rates in patients with the high PD-1 expression in the tumour nest and in the tumour periphery were 54.6% and 67.7%, respectively, which were significantly lower than those in their counterparts (79.4%, P < 0.001; 80.0%, P = 0.04). The 5 year cancer-specific survival rates in patients with the high PD-1 expression in the tumour nest and the tumour periphery were 69.1% and 75.7%, respectively, which were significantly lower than those in their counterparts (84.7%, P = 0.007; 87.8%, P = 0.01). A multivariate Cox regression analysis identified the high PD-1 expression in the tumour nest (hazard ratio 3.07, P < 0.001; hazard ratio 2.44, P = 0.011) and positive lymphovascular invasion (hazard ratio 4.86, P < 0.001; hazard ratio 4.03, P < 0.001) as independent predictors of disease progression and of cancer death, respectively. CONCLUSIONS: PD-1 positivity in the tumour nest could be a strong predictor for a worse clinical outcome and may be a useful indicator for selecting appropriate candidates for adjuvant therapy such as chemotherapy in upper tract urothelial carcinoma patients treated with radical nephroureterectomy.

Clinical and prognostic significance of bone marrow abnormalities in the appendicular skeleton detected by low-dose whole-body multidetector computed tomography in patients with multiple myeloma.

Clinical significance of medullary abnormalities in the appendicular skeleton (AS) detected by low-dose whole-body multidetector computed tomography (MDCT) in patients with multiple myeloma (MM) was investigated. A total of 172 patients with monoclonal gammopathy of undetermined significance (MGUS) (n=17), smoldering MM (n=47) and symptomatic MM (n=108) underwent low-dose MDCT. CT values (CTv) of medullary density of AS⩾0 Hounsfield unit (HU) was considered as abnormal. Percentage of medullary abnormalities and the mean CTv of AS in patients with MGUS, smoldering MM and symptomatic MM were 18, 55 and 62% and -44.5 , -20.3 and 11.2 HU, respectively (P<0.001 and P<0.001). Disease progression of MM was independently associated with high CTv on multivariate analysis. In symptomatic MM, the presence of abnormal medullary lesions was associated with increased incidence of high-risk cytogenetic abnormalities (34.4% vs 7.7%; P=0.002) and extramedullary disease (10.4% vs 0%; P=0.032). It was also an independent poor prognostic predictor (hazard ratio 3.546, P=0.04). This study showed that CTv of AS by MDCT is correlated with disease progression of MM, and the presence of abnormal medullary lesions is a predictor for poor survival.

Percentage of urinary albumin excretion and serum-free light-chain reduction are important determinants of renal response in myeloma patients with moderate to severe renal impairment.

Reversal of renal dysfunction significantly affects the prognosis of multiple myeloma (MM) with renal impairment (RI). There is no reliable test for predicting reversibility of RI in MM patients. We postulated that MM with high albuminuria may reflect glomerular disease that is difficult to reverse. Here, we examined the impact of urinary albumin excretion. We retrospectively analyzed 279 patients admitted to our hospital from April 2000 to December 2013. Clinical variables and laboratory data that may affect myeloma treatment response were extracted. The results were examined for relationship to renal response by univariate and multivariate analysis. RI (estimated glomerular filtration rate ≦50 ml/min per 1.73 m(2)) was observed in 116 patients (46%) and renal responses of renal complete response, renal partial response, renal minor response and no response were obtained in 46 (40%), 15 (13%), 13 (11%) and 42 (36%) patients, respectively. Although renal recovery was significantly associated with Durie-Salmon 1 or 2 (P=0.02), myeloma response better than very good partial response (P=0.03), involved free light-chain (iFLC) reduction from baseline 80% at day 12 (P=0.005), ≧95% at day 21 (P<0.001) and urinary albumin ≦25% on admission (P<0.001) on univariate analysis, only reduction of iFLC 95% at day 21 (P=0.015) and urinary albumin ≦25% (P=0.007) remained significant for any renal response. Our observation indicates that increased urinary albumin excretion >25% and reduction of iFLC ≦95% on day 21 were associated with favorable renal recovery in MM patients with RI, and were considered as negative predictors for renal response.

Antidepressant and anxiolytic profiles of newly synthesized arginine vasopressin V1B receptor antagonists: TASP0233278 and TASP0390325.

BACKGROUND AND PURPOSE: Vasopressin V1B receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine vasopressin receptor 1B (V1B receptor) antagonists, TASP0233278 and TASP0390325. EXPERIMENTAL APPROACH: We investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models. KEY RESULTS: Both TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V1B receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V1B receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats). CONCLUSION: TASP0233278 and TASP0390325 are potent and orally active V1B receptor antagonists with antidepressant and anxiolytic activities in rodents.

Time to first cigarette and lung cancer risk in Japan.

BACKGROUND: Cigarette smoking is the major cause of lung cancer (LC). Although the time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, little information is available on its possible relation to LC. PATIENTS AND METHODS: This case-control study includes a total of 1572 incident LC cases and 1572 non-cancer controls visiting for the first time the Aichi Cancer Center Hospital between 2001 and 2005. We estimated the odds ratio (OR) and 95% confidence interval (CI) for TTFC using a logistic regression model after adjustment for several potential confounders. RESULTS: TTFC was inversely associated with the risk of LC. This association was consistent across histological subtypes of LC. For all LCs considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC >60 min, the adjusted ORs were 1.08 (95% CI, 0.73-1.61) for TTFC of 31-60 min, 1.40 (0.98-2.01) for 6-30 min and 1.86 (1.28-2.71) for within 5 min (Ptrend, < 0.001). Statistically marginally significant heterogeneity by histological subtype was observed (Pheterogeneity, 0.002). CONCLUSIONS: Nicotine dependence, as indicated by the TTFC, is associated with increased risk of LC and is therefore an independent marker of exposure to tobacco smoking.

Quantitative analysis of deuterium in zircaloy using double-pulse laser-induced breakdown spectrometry (LIBS) and helium gas plasma without a sample chamber.

A crucial safety measure to be strictly observed in the operation of heavy-water nuclear power plants is the mandatory regular inspection of the concentration of deuterium penetrated into the zircaloy fuel vessels. The existing standard method requires a tedious, destructive, and costly sample preparation process involving the removal of the remaining fuel in the vessel and melting away part of the zircaloy pipe. An alternative method of orthogonal dual-pulse laser-induced breakdown spectrometry (LIBS) is proposed by employing flowing atmospheric helium gas without the use of a sample chamber. The special setup of ps and ns laser systems, operated for the separate ablation of the sample target and the generation of helium gas plasma, respectively, with properly controlled relative timing, has succeeded in producing the desired sharp D I 656.10 nm emission line with effective suppression of the interfering H I 656.28 nm emission by operating the ps ablation laser at very low output energy of 26 mJ and 1 µs ahead of the helium plasma generation. Under this optimal experimental condition, a linear calibration line is attained with practically zero intercept and a 20 µg/g detection limit for D analysis of zircaloy sample while creating a crater only 10 µm in diameter. Therefore, this method promises its potential application for the practical, in situ, and virtually nondestructive quantitative microarea analysis of D, thereby supporting the more-efficient operation and maintenance of heavy-water nuclear power plants. Furthermore, it will also meet the anticipated needs of future nuclear fusion power plants, as well as other important fields of application in the foreseeable future.

Cor triatriatum sinister: an incidental finding in a patient with paroxysmal atrial fibrillation.

A 58-year-old male was referred for catheter ablation for atrial fibrillation. He was incidentally diagnosed with cor triatriatum sinister by preoperative transesophageal echocardiography and cardiovascular computed tomography. The patient has since been free from atrial fibrillation for over 24 months following successful electrical pulmonary vein isolation. The rapidly soaring number of cases undergoing catheter ablation for atrial fibrillation and imaging investigation prior to the procedure may increase the incidental detection of asymptomatic congenital heart diseases.

The effect of group-based lifestyle interventions on risk factors and insulin resistance in subjects at risk for metabolic syndrome: the Tabaruzaka Study 1.

AIM: The aim of this study was to evaluate the efficacy of two group-based lifestyle interventions in ameliorating the risk factors of metabolic syndrome (MS) and insulin resistance. METHODS: Ninety-eight subjects who had at least one component of MS were randomized into standard intervention (SI) (4-month intervention; n = 50) and extended intervention (EI) (10-month intervention; n = 48) groups, and 39 subjects were followed up for a control group. The effects of intervention were evaluated after 10, 22 and 34 months. RESULTS: At month 10, the standard and EI groups showed improved body mass index (BMI) (SI, -0.28; EI, -0.47; control, -0.09), high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and A1c and a decreased mean number of components of MS (SI, -0.37; EI, -0.51; control, 0.08). At month 34, the effects on BMI (SI, -0.66; EI, -0.60; control, -0.05) and HDL-cholesterol were sustained for both the intervention groups. In controls, the increases in fasting plasma glucose and the mean number of components of MS from the baseline to month 34 were greater than those in the standard and EI groups. Whole body insulin sensitivity index and hepatic insulin resistance index were also improved at month 10. CONCLUSIONS: Group-based lifestyle intervention could be an efficient way to prevent MS. Its effects were sustainable, at least in part, for 2 years. These effects may be mediated by an improvement in insulin sensitivity.

Detrimental effects of glucocorticoids on neuronal migration during brain development.

Glucocorticoids, the most downstream effectors of the hypothalamus-pituitary-adrenal axis, are one of main mediators of the stress reaction. Indeed, exposure to high levels of stress-triggered glucocorticoids is detrimental to brain development associated with abnormal behaviors in experimental animals and the risk of psychiatric disorders in humans. Despite the wealth of this knowledge, the cellular and molecular mechanisms underlying the detrimental effects of glucocorticoids on brain development remain unclear. Here, we show that excess glucocorticoids retard the radial migration of post-mitotic neurons during the development of the cerebral cortex, and identify an actin regulatory protein, caldesmon, as the glucocorticoids' main target. The upregulation of caldesmon expression is mediated by glucocorticoid receptor-dependent transcription of the CALD1 gene encoding caldesmon. This upregulated caldesmon negatively controls the function of myosin II, leading to changes in cell shape and migration. The depletion of caldesmon in vivo impairs radial migration. The overexpression of caldesmon also causes delayed radial migration during cortical development, mimicking the excessive glucocorticoid-induced retardation of radial migration. We conclude that an appropriate range of caldesmon expression is critical for radial migration, and that its overexpression induced by excess glucocorticoid retards radial migration during cortical development. Thus, this study provides a novel insight into the underlying mechanism of glucocorticoid-related neurodevelopmental disorders.

Inhibition of Bach1 ameliorates indomethacin-induced intestinal injury in mice.

BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). It plays an important role in the feedback regulation of HO-1 expression, which protects cells from various insults including oxidative stress and inflammatory cytokines. However, the role of Bach1 in intestinal inflammation remains unclear. In this study, the role of Bach1 in intestinal mucosal injury was elucidated using 8-week-old female C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice. Intestinal mucosal injuries induced by a single subcutaneous administration of indomethacin were evaluated macroscopically, histologically, and biochemically. Mucosal protein content and chemokine mRNA levels were determined by real-time PCR. Our results showed that the indomethacin-induced intestinal injury was remarkably improved in Bach1-deficient mice. Histological examination showed that the area of injured lesion was decreased in Bach1-deficient mice compared to wild-type mice. Administration of indomethacin induced expression of inflammatory chemokines such as KC, MIP1alpha and MCP1, which was suppressed in Bach1-deficient mice. Myeloperoxidase activity in the intestinal mucosa was also significantly decreased in Bach1-deficient mice. Additionally, Bach1 deficiency enhanced immunopositivity of HO-1 in the intestinal mucosa after indomethacin administration. Disruption of the Bach1 gene thus caused inhibition of mucosal injury, indicating that inhibition of Bach1 may be a novel therapeutic strategy for treating indomethacin-induced intestinal injury.

Dynamics of magnetic domain wall motion after nucleation: dependence on the wall energy.

The dynamics of magnetic domain wall motion in the FeNi layer of a FeNi/Al2O3/Co trilayer has been investigated by a combination of x-ray magnetic circular dichroism, photoelectron emission microscopy, and a stroboscopic pump-probe technique. The nucleation of domains and subsequent expansion by domain wall motion in the FeNi layer during nanosecond-long magnetic field pulses was observed in the viscous regime up to the Walker limit field. We attribute an observed delay of domain expansion to the influence of the domain wall energy that acts against the domain expansion and that plays an important role when domains are small.

Methionine-rich storage protein gene in the rice stem borer, Chilo suppressalis, is expressed during diapause in response to cold acclimation.

Gene expressions of acclimatized and non-acclimatized diapausing larvae were examined in Chilo suppressalis using a subtraction technique. A gene encoding a methionine-rich storage protein, CsSP1, was cloned and its complete cDNA sequence was determined. Potentially, CsSP1 encoded a 758-amino acid protein, with a calculated molecular weight of 88.8 kDa. The expression level of CsSP1 was higher in nondiapausing larvae than in diapausing ones. The CsSP1 expression was up-regulated in diapausing larvae when the temperature of cold acclimation was shifted to 5 degrees C. The up-regulated level was maintained at 40 days after incubation at 5 degrees C. In nondiapausing larvae, CsSP1 expression was down-regulated when the temperature was below developmental zero. Involvement of CsSP1 in diapause, cold tolerance acquisition and postdiapause development in C. suppressalis is discussed.

Usefulness of sparfloxacin against Chlamydia pneumoniae infection in patients with bronchial asthma.

The efficacy of sparfloxacin (SPFX) for the control of bronchial asthma was evaluated in 26 patients with suspected Chlamydia pneumoniae infection. Patients were randomly allocated to receive SPFX 200 mg/day (n = 14) or control treatment (n = 12) for 21 days. Significant improvements in serum C-reactive protein levels, and significant decreases in peripheral eosinophil counts, serum eosinophil cationic protein (ECP) and sputum ECP were observed in the SPFX-treated group at day 21. SPFX-treated patients also had a significantly reduced frequency of asthma symptoms, reduced inhalant beta2-stimulant use, and significant increases in morning peak expiratory flow. At the end of the study, C. pneumoniae was undetectable in two SPFX-treated patients who underwent polymerase chain reaction testing, but one control patient who was tested still had detectable levels of C. pneumoniae. These results suggest that SPFX could be used to control bronchial asthma in patients with suspected persistent C. pneumoniae infection.